Hydromorphone is an analgesic with its principal therapeutic effect, the relief of pain. The precise mechanism of action of hydromorphone is not medically understood, although it is thought to relate to the existence of hydromorphone receptors in the central nervous system. Generally, the analgesic action of parenterally administered hydromorphone is apparent within fifteen minutes and the onset of action of orally administered hydromorphone is somewhat slower, with analgesia occurring within thirty minutes. In human plasma, the half-life of hydromorphone is about two and one-half hours. Hydromorphone is indicated for the relief of moderate to severe pain, such as pain due to infection, surgery, cancer, trauma, biliary colic, disease, renal colic, myocardial infarction, and burns. A pharmaceutically-acceptable dosage form for oral administering hydromorphone to provide analgesic therapy beyond its short half-life at a controlled-rate over an extended period of time appears to be lacking in the pharmaceutical and medical arts. The pharmacological and medical properties of hydromorphone are known in Pharmaceutical Sciences, Remington, 17th Ed., pp. 1099-1044, (1985); and in the Pharmacological Basis of Therapeutics, Goodman and Rall, 8th Ed., pp. 485-518, (1990).
The present invention unexpectedly provides both a dosage form comprising hydromorphone and a therapeutic composition comprising hydromorphone for the management of pain. That is, the prior art did not appreciate that hydromorphone, which is a complex chemical 4,5-expoxy-3-hydroxy-17-methyl-morphinan-6-one, comprising five rings substituted with different chemical groups, can be made into a continuous release dosage form, or into a therapeutic composition. The prior did not appreciate a dosage form and a therapeutic composition can be made available comprising an osmogel such as a polyalkylene oxide and other ingredients including an osmagent. The prior art did not make obvious hydromorphone formulated with a polyalkylene oxide, as the mechanism which controlled the release of hydromorphone from polyalkylene oxide are complex polymers. For example, the hydromorphone could become immobile and trapped in the polyalkylene oxide, also, the polyalkylene oxide could exhibit unacceptable swelling in the presence of aqueous including biological fluid and thereby change the rate of release of the hydromorphone from the polyalkylene oxide. Further, the osmogel such as polyalkylene oxide, can possess a glass-transition temperature below human body temperature, which leads away from using hydromorphone in such an environment. Additionally, the properties of hydromorphone and polyalkylene oxide, exemplified by the crystallinity of hydromorphone in polyalkylene oxide, the burst or lag effect of hydromorphone in polyalkylene oxide, the hydromorphone solubility in a polyalkylene oxide hydrogel all attest to the nonobviousness of the present invention.
Prior to this invention, hydromorphone was administered in conventional forms, such as a nonrate-controlling dose-dumping tablet or by a dose-dumping capsule, and usually at multiple, repetitive dosing intervals. This prior-art mode of therapy leads to an initial high dose of hydromorphone in the blood, followed by a decreased dose of hydromorphone in the blood. The concentration differences in dosing patterns are related to the presence and absence of administered drug, which is a major disadvantage associated with conventional dosage forms. Conventional dosage forms and their mode of operation, including dose peaks and valleys, are discussed in Pharmaceutical Sciences, Remington, 18th Ed., pp 1676-1686, (1990), Mark Publishing Co.; The Pharmaceutical and Clinical Pharmacokinetics, 3rd Ed., pp 1-28, (1984), Lea and Febiger, Philadelphia.; and in U.S. Pat. Nos. 3,598,122 and 3,598,123, both issued to Zaffaroni.
The above presentation dictates of the critical need for a dosage form and for a therapeutic composition that overcomes the shortcomings of conventional dosage forms, including tablets, capsules, elixirs and suspensions. These conventional dosage forms and their accompanying peaks and valleys do not provide for dose-regulated drug therapy over an extended period of time. The hydromorphone as delivered by the prior art is often dosed two or more times a day, which does not lend itself to controlled and sustained therapy. This prior-art pattern of drug administration speaks of the need for a dosage form and for a therapeutic composition that can administer hydromorphone in a rate-controlled dose over an extended time to provide constant therapy, and thereby eliminate the peaks, valleys, and multiple uncontrolled dosing of the prior art.
In view of the foregoing presentation, it is immediately apparent that a serious need exists for an improvement in the delivery of hydromorphone for its therapeutic analgesic effect. The need exists to provide a novel therapeutic composition comprising hydromorphone, and the need exists to provide a novel method of administering hydromorphone to a patient in need of hydromorphone therapy. The invention provides an oral, relatively-easy to administer mode and manner of hydromorphone therapy.